Andrea Donti

Management of Pulmonary Arterial Hypertension Associated with Congenital Systemic-to-Pulmonary Shunts and Eisenmenger’s Syndrome

A large proportion of patients with congenital heart disease (CHD), in particular those with relevant systemic-to-pulmonary shunts, will develop pulmonary arterial hypertension (PAH) if left untreated. Persistent exposure of the pulmonary vasculature to increased blood flow, as well as increased pressure, may result in pulmonary obstructive arteriopathy, which leads to increased pulmonary vascular resistance that, if it approaches or exceeds systemic resistance, will result in shunt reversal. Eisenmenger’s syndrome, the most advanced form of PAH associated with CHD, is defined as CHD with an initial large systemic-to-pulmonary shunt that induces severe pulmonary vascular disease and PAH, with resultant reversal of the shunt and central cyanosis.The histopathological and pathobiological changes seen in patients with PAH associated with congenital systemic-to-pulmonary shunts, such as endothelial dysfunction of the pulmonary vasculature, are considered similar to those observed in idiopathic or other associated forms of PAH. A pathological and pathophysiological classification of CHD with systemic-to-pulmonary shunt leading to PAH has been developed that includes specific characteristics, such as the type, dimensions and direction of the shunt, extracardiac abnormalities and repair status. A clinically oriented classification has also been proposed.The prevalence of PAH associated with congenital systemic-to-pulmonary shunts in Western countries has been estimated to range between 1.6 and 12.5 cases per million adults, with 25–50% of this population affected by Eisenmenger’s syndrome.Clinically, Eisenmenger’s syndrome presents with multiple organ involvement, with progressive deterioration of function over time. The signs and symptoms of Eisenmenger’s syndrome in the advanced stages include central cyanosis, dyspnoea, fatigue, haemoptysis, syncope and right-sided heart failure. Survival of patients with Eisenmenger’s syndrome is clearly less than that of the general population, but appears to be better than that of patients with idiopathic PAH in a comparable functional class.The treatment strategy for patients with PAH associated with congenital systemic-to-pulmonary shunts and, in particular, those with Eisenmenger’s syndrome is based mainly on clinical experience rather than being evidence based. General measures include recommendations for physical activity, pregnancy, infections, air travel, exposure to high altitudes and elective surgery, and that psychological assistance be provided as necessary. Phlebotomies are required only when hyperviscosity of the blood is evident, usually when the haematocrit is >65%. The use of supplemental oxygen therapy is controversial and it should be used only in patients in whom it produces a consistent increase in arterial oxygen saturation. Oral anticoagulant treatment with warfarin can be initiated in patients with pulmonary artery thrombosis and absent, or only mild, haemoptysis.The following three classes of drugs targeting the correction of abnormalities in endothelial dysfunction have been approved recently for the treatment of PAH: (i) prostanoids; (ii) endothelin receptor antagonists; and (iii) phosphodiesterase-5 inhibitors. The efficacy and safety of these compounds have been confirmed in uncontrolled studies in patients with PAH associated with corrected and uncorrected congenital systemic-to-pulmonary shunts, as well as in patients with Eisenmenger’s syndrome. One randomized controlled trial reported favourable short- and long-term outcomes of treatment with the orally active dual endothelin receptor antagonist bosentan in patients with Eisenmenger’s syndrome. Lung transplantation with repair of the cardiac defect or combined heart-lung transplantation are options for Eisenmenger’s syndrome patients with a poor prognosis. A treatment algorithm based on the one used in the treatment of PAH patients is proposed for patients with PAH associated with corrected and uncorrected congenital systemic-to-pulmonary shunts and Eisenmenger’s syndrome.

Melody transcatheter pulmonary valve implantation. Results from the registry of the Italian society of pediatric cardiology

Percutaneous implantation of pulmonary valve has been recently introduced in the clinical practice. Our aim was to analyze data of patients treated in Italy by using the Melody Medtronic valve.

A pilot study on the effects of carvedilol on right ventricular remodelling and exercise tolerance in patients with systemic right ventricle

BACKGROUND Patients with atrial repair for transposition of the great arteries and patients with congenitally corrected transposition have a right ventricle (RV) in the systemic position and they may develop RV dysfunction and exercise intolerance with advancing age. No data is available on the effect of carvedilol in patients with dysfunctional systemic RV. METHODS We studied with cardiovascular magnetic resonance (CMR), cardiopulmonary exercise testing, and standard 12-leads electrocardiogram, 8 adults (median age 26 years, range 18-31) with chronic stable heart failure and systemic RV dysfunction (6 patients with atrial repair and 2 patients with congenitally corrected transposition). Assessment was done before and after 12 months of carvedilol administration. The initial dose was 3.125 mg twice daily, and the target dose was 25 mg twice a day. RESULTS Carvedilol administration was safe and the target dose was achieved in 5/8 (62%) patients. Right ventricular end-diastolic (119 ± 31 vs. 112 ± 28 ml/m², p=0.01) and end-systolic volumes decreased (79 ± 17 vs. 65 ± 14 ml/m², p=0.006), and RV ejection fraction improved (34 ± 6 vs. 42 ± 7%, p=0.004). Left ventricular ejection fraction increased (44 ± 8 vs. 49 ± 9%, p=0.01), suggesting a positive biventricular remodelling. Peak oxygen uptake did not change with carvedilol (26.8 ± 5.3 vs. 27.3 ± 5.7 ml O₂/Kg/min, p=0.58), whereas exercise duration increased (13.4 ± 2.6 vs. 17.3 ± 3.1 min, p=0.008). CONCLUSIONS In this small cohort, carvedilol administration was safe and it was associated with positive RV remodelling as well as improved exercise duration.

Impact of pulmonary regurgitation and right ventricular dysfunction on oxygen uptake recovery kinetics in repaired tetralogy of Fallot

Patients with repaired tetralogy of Fallot (ToF) featuring severe pulmonary regurgitation (PR) and/or right ventricular (RV) dysfunction have reduced exercise tolerance.

Long-term incidence of atrial fibrillation and flutter after transcatheter atrial septal defect closure in adults

BACKGROUND The long-term risk of atrial fibrillation and flutter (AFF) after trascatheter atrial septal defects (ASD) closure in adults is unknown. METHODS We studied 134 patients who have undergone transcatheter ASD closure at our institution at an age of > 18 years (mean age 39 +/- 16 years); Patients were followed-up for 4.8 +/- 2.7 years (range 0.8-9.6 years). We assessed the presence of AFF both before and after ASD closure using standard 12 lead ECGs or 24h ambulatory Holter monitors. RESULTS 13 patients (10%) had documented AFF before the procedure (paroxysmal in 6, permanent in 7). Patients with AFF before the procedure were older (p < 0.0001), and had worse clinical condition (p = 0.0008). Patients without a history of AFF before the procedure and those who experienced paroxysmal AFF before the procedure had a very low annual risk (0%) of subsequent permanent AFF at long-term follow-up. Four patients with permanent AFF before the procedure (onset of < 12months) underwent electrical cardioversion immediately before ASD closure. Two of them (50%) are in sinus rhythm after 4.1 and 7.0 years, respectively. CONCLUSIONS Transcatheter ASD closure performed in adults with no history of AFF or with a history of paroxysmal AFF before closure seems to protect from development of AFF in the long-term. In selected patients with permanent AFF at closure, device ASD closure together with arrhythmia cardioversion might be able to restore and maintain sinus rhythm in the long-term.

Long-term efficacy of transcatheter patent foramen ovale closure on migraine headache with aura and recurrent stroke.

Objectives: To assess the long‐term results of transcatheter patent foramen ovale (PFO) closure on migraine headache with aura (MHA) and on the risk of recurrent stroke. Background: Transcatheter PFO closure is associated with an early improvement of MHA, and a reduction or the risk of recurrent cerebral ischemia, but the long‐term outcome after the procedure is unknown. Methods: We analyzed follow‐up data of 38 consecutive patients who had undergone transcatheter PFO closure at our institution because of cryptogenic stroke and had been followed‐up for at least 3 years after the procedure. Mean age at closure was 43 ± 13 years. Thirteen patients (34%) had a diagnosis of MHA made by the primary care physician or the referring neurologist. Migraine disability assessment questionnaire (MIDAS) was used to assess MHA incidence and severity. Results: After a mean follow‐up of 4.8 ± 1.4 years, two patients had a recurrent stroke (13 and 15 months after the procedure, respectively). Recurrence rate 5 years after the procedure was 5.3%. After 4.9 ± 1.4 years from the intervention, 12/13 patients (92%, 95% CI 65–99%) had complete resolution in their MHA. Overall, MIDAS score decreased significantly (38.6 ± 26.3 vs. 4.4 ± 5.1, P < 0.0001) after the procedure. One patient did not report any improvement of MHA after transcatheter PFO closure, whereas one patient reported a severe relapse of MHA about 1 year after PFO closure. Freedom from recurrent MHA 5 years after the procedure was 85% (95% CI 57–97%). Conclusions: The rate of recurrent cerebral ischemia and recurrent MHA seems to be low at long‐term follow‐up after transcatheter PFO closure. Recurrent cerebral ischemia and relapse of MHA seem to be confined to the first 15 months after the procedure.© 2006 Wiley‐Liss, Inc.

Transcatheter patent foramen ovale closure using the premere PFO occlusion system

Objectives: To evaluate the safety and efficacy profile of the new Premere patent foramen ovale (PFO) occlusion system. Background: Several different devices have been used so far for transcatheter PFO closure but no data has been published so far on the efficacy and safety of the Premere PFO occlusion system. Methods: Since September 2005, 15 patients (seven males, eight females; mean age 51.2 ± 10.8 years) at our institution underwent transcatheter PFO closure because of cryptogenic stroke, using the Premere PFO occlusion system. The procedure was performed under fluoroscopic and transesophageal echocardiographic (TEE) guidance in all patients. Seven patients (47%) had an associated atrial septal aneurysm and two patients had had >1 stroke. Five patients (33%) had an associated thrombophilia, whereas three patients (20%) had a diagnosis of migraine headache with aura, by the referring neurologist. Residual shunt was assessed immediately after and 1 month (only in 11 patients) after the procedure by both transcranial Doppler and TEE. Results: Premere PFO devices could be implanted in all patients (20 mm size in seven patients, 25 mm size in eight). Fluoroscopy time was 7.3 ± 1.9 and procedural time was 11 ± 3 min (range 7–17 min), reflecting our initial learning curve with this device. No complication occurred during the procedure or at follow‐up. A residual shunt was noted immediately after the procedure in eight patients (53%) and at 1 month in 4/11 patients (36%). Residual shunt was mild in all patients. After a median follow‐up of 4.2 months (0.2–5.8 months), no patient had a recurrent stroke. All patients with migraine headache with aura had resolution of symptoms. Conclusions: Our preliminary experience with the Premere PFO occlusion system shows that this device is safe and effective.

Management of patients with patent foramen ovale and cryptogenic stroke: a collaborative, multidisciplinary, position paper: executive summary.

Objectives: To organize a common approach on the management of patent foramen ovale (PFO) and cryptogenic stroke that may be shared by different specialists. Background: The management of PFO related to cryptogenic stroke is controversial, despite an increase in interventional closure procedures. Methods: A consensus statement was developed by approaching Italian national cardiological, neurological, and hematological scientific societies. Task force members were identified by the president and/or the boards of each relevant scientific society or working group, as appropriate. Drafts were outlined by specific task force working groups. To obtain a widespread consensus, these drafts were merged and distributed to the scientific societies for local evaluation and revision by as many experts as possible. The ensuing final draft, merging all the revisions, was reviewed by the task force and finally approved by scientific societies. Results: Definitions of transient ischemic attack and both symptomatic and asymptomatic cryptogenic strokes were specified. A diagnostic workout was identified for patients with candidate event(s) and patient foramen ovale to define the probable pathogenesis of clinical events and to describe individual PFO characteristics. Further recommendations were provided regarding medical and interventional therapy considering individual risk factors of recurrence. Finally, follow‐up evaluation was appraised. Conclusions: Available data provided the basis for a shared approach to management of cryptogenic ischemic cerebral events and PFO among different Italian scientific societies. Wider international initiatives on the topic are awaited.

Modulation of neurohormonal activity after treatment of children in heart failure with carvedilol

BACKGROUND In adults with heart failure, neurohormonal overstimulation is related to the progression of the disease, and influences prognosis. beta-blockers, which modulate neurohormonal activation, now play an essential role in the pharmacological management of heart failure in adults, but their use in children is very limited. PATIENTS AND METHODS To investigate the effects of carvedilol administration on neurohormonal activation and left ventricular function, carvedilol was added to standard treatment for heart failure in 9 patients with dilated cardiomyopathy due to heart muscle disease. Standard treatment has been in place for at least 1 month. The protocol consisted in a baseline evaluation to assess neurohormonal activation, and echocardiographic evaluation of left ventricular function. This was followed by a final evaluation at 12 months from carvedilol loading. Carvedilol was started at 0.05 mg/kg/day, and increased every two weeks until the target dose of 0.8 mg/kg/day was reached. RESULTS Carvedilol administration was associated with a significant reduction in plasma norepinephrine (p = 0.00001), dopamine (p = 0.0001), aldosterone (p = 0.00001) and activation of the renin-angiotensin system (p = 0.0006). Similar reductions in vanilmandelic and homovanillic acid were noted. After 12 months, a positive remodeling took place, with significant reductions in end-diastolic (p = 0.004) and end-systolic diameters (p = 0.009), and an increase in left ventricular ejection fraction (p = 0.001). No adverse effects needing reduction or interruption in the dosage were noted in the run-in phase, nor in the period of maintenance. CONCLUSION Carvedilol is a safe complement to standard therapy for heart failure in children, allowing a significant reduction of neurohormonal activation with evident benefits on both ventricular function and the clinical condition.

Management of patients with patent foramen ovale and cryptogenic stroke: A collaborative, multidisciplinary, position paper

Objectives: To organize a common approach on the management of patent foramen ovale (PFO) and cryptogenic stroke that may be shared by different specialists. Background: The management of PFO related to cryptogenic stroke is controversial, despite an increase in interventional closure procedures. Methods: A consensus statement was developed by approaching Italian national cardiological, neurological, and hematological scientific societies. Task force members were identified by the president and/or the boards of each relevant scientific society or working group, as appropriate. Drafts were outlined by specific task force working groups. To obtain a widespread consensus, these drafts were merged and distributed to the scientific societies for local evaluation and revision by as many experts as possible. The ensuing final draft, merging all the revisions, was reviewed by the task force and finally approved by scientific societies. Results: Definitions of transient ischemic attack and both symptomatic and asymptomatic cryptogenic strokes were specified. A diagnostic workout was identified for patients with candidate event(s) and patient foramen ovale to define the probable pathogenesis of clinical events and to describe individual PFO characteristics. Further recommendations were provided regarding medical and interventional therapy considering individual risk factors of recurrence. Finally, follow‐up evaluation was appraised. Conclusions: Available data provided the basis for a shared approach to management of cryptogenic ischemic cerebral events and PFO among different Italian scientific societies. Wider international initiatives on the topic are awaited.